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    DEMETON-S-METHYL AND RELATED COMPOUNDS       JMPR 1973

    (DEMETON-S-METHYL, DEMETON-S-METHYL SULFOXIDE AND
    DEMETON-S-METHYL SULFONE)

    Explanation

         One member of this family of compounds, oxydemeton-methyl
    (Demeton-S-methyl sulfoxide), was reviewed at several previous
    meetings (FAO/WHO, 1965b; 1968b; 1969b). On the basis of the studies
    available at that time, primarily short-term studies, an acceptable
    daily intake for man was estimated to be 0-0.0025 mg/kg/day (FAO/WHO,
    1965b). When further considered at the 1967 meeting new data,
    primarily a threegeneration reproduction study, was reviewed and the
    ADI for man again reaffirmed to be 0-0.0025 mg/kg/day (FAO/WHO,
    1968b). The 1968 joint meeting re-evaluated this compound and
    concluded that the available information revealed that the toxicology
    was not related to a single defined compound nor was there precise
    knowledge of materials actually used in agricultural practice
    (FAO/WHO, 1969b). Furthermore, no long-term data on any of the
    substances belonging to this group were available for evaluation. That
    meeting, therefore, recommended that the ADI as established at
    previous meetings should no longer be considered valid. The further
    work required to allow full assessment to be made included:
    specifications of the compound or compounds in actual agricultural
    use; studies to compare the metabolic fate in animals, plants and man;
    investigation of the cholinesterase inhibition in man and adequate
    long-term studies in two species. Portions of these requirements have
    been met and the new work has been summarized combined with that
    previously published and discussed in the following monograph
    addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    Biochemical aspects

    Absorption, distribution and excretion

         Studies on the absorption, distribution and excretion of the
    demeton-methyl family of compounds is limited to a study on the oral
    and subcutaneous administration of oxydemetonmethyl to mice. Within 15
    hours following either oral or subcutaneous dosing at a level of 10
    mg/kg, 97% of the administered dose was eliminated from the body
    within 15 hours. There was no indication of the metabolic fate of the
    compound in this study (Muhlmann and Tietz, 1956).

    Information on identity and properties

    Demeton-S-methyl

    Chemical            O, O-dimethyl-S-/2-(ethyl-thio)-ethyl/
    name:               phosphorothioate

    Synonyms:           Metasystox (i)
                        Metaisosystox
                        Bayer 18 436
                        25/154
                        E 154
                        Metilmerkaptofos teolovi (common name in USSR)

    Structural                O
    formula             CH3O  "
                            \"
                              P-S-CH2-CH2-S-C2H5
                            /
                        CH3O

    Empirical           C6H15O3PS2
    formula:

    Appearance and      Pale yellowish oily liquid with penetrating odour
    odour:              reminiscent of leeks

    Molecular           230.3
    weight:

    Boiling point:      74°C at 0.05 mm Hg
                        92°C at 0.20 mm Hg
                        102°C at 0.4 mm Hg
                        118°C at 1.0 mm Hg

    Vapour              1.2 x 10-4 mm Hg at 10°C
    pressure:           3.6 x 10-4 mm Hg at 20°C
                        1.05 x 10-3 mm Hg at 30°C
                        2.9 X 10-3 mm Hg at 40°C

    Volatility:         1.6 mg/m3 at 10°C
                        4.5 mg/m3 at 20°C
                        12.4 mg/m3 at 30°c
                        34.0 mg/m3 at 40°C

    Specific            1.21 at 20°C
    gravity:                     

    Solubility:         Approx. 3300 mg/litre in water at room temperature;
                        readily soluble in most organic solvents; limited
                        solubility in petroleum ether

    Minimum      
    purity:             90%

    Impurities:         O,O,S-trimethylthiophosphate      max. 1.5%
                        O-methyl-S-2-(ethylmercapto)-ethylthiophosphate
                                                          max. 3.0%
                        2-ethylthioethylmercaptan         max. 0.8%
                        bis(2-ethylthioethyl)-disulfide   max. 0.8%
                        Various ionic components
                        (sulfonium compounds,             max. 2.5%
                        anorganic salts                   altogether
                        Oligomeric alkyl(thio)            max 1.0%
                        phosphates                        altogether
                        Water                             max. 0.4%

    Oxydemeton-methyl

    Chemical
    name:     O,O-dimethyl-S-/2-(ethyl-sulfinyl)-ethyl/phosphorothioate

    Synonyms:           Metasystox R
                        Demeton-S-methylsulfoxide
                        Bayer 21 097
                        R 2170
                        Metaisosystoxsulfoxide
                        Metilmerkaptofosoksid (common name in USSR)

    Structural               O           O
    formula             CH3O "           "
                            \"           "
                             P-S-CH2-CH2-S-C2H5
                            /
                       CH3O

    Empirical           C6H15O4PS2
    formula:

    Appearance and      Yellowish liquid, practically odourless
    odour:

    Molecular
    weight:             246.3

    Boiling point:      106°C at 0.01 mm Hg

    Volatility:         0.09 mg/m3 at 20°C
                        0.3 mg/m3 at 30°C
                        0.7 mg/m3 at 40°C

    Specific
    gravity:            1.289 at 20°C
                                  

    Solubility:         Miscible with water in any ratio; soluble in most
                        organic solvents, but practically insoluble in
                        petroleum ether

    Minimum             
    purity:             90%

    Impurities:         Demeton-S-methyl                  max. 2.0%
                        Demeton-S-methylsulfone           max. 2.0%
                        O,O,S-trimethylthiophosphate      max. 1.5%
                        O-methyl-S-2-(ethylsulfinyl)ethylthio-phosphate
                                                          max. 1.2%
                        bis(2-ethylsulfinylethyl)-disulfide
                                                          max. 0.5%
                        Various ionic components          max. 0.5%
                        (sulfonium compounds, etc.)       altogether
                        Sodium- and ammoniumsulfate       max. 0.8%
                                                          altogether
                        Oligomeric alkyl(thio)phosphates  max. 0.5%
                                                          altogether
                        Water                             max. 1.0%

    Demeton-S-Methylsulfone

    Chemical
    name:     O,O-dimethyl-S-/2-(ethyl-sulfonyl)-ethyl/phosphorothioate

    Synonyms:           Metaisosystoxsulfon
                        Bayer 20 315
                        M 3/158
                        E 158

    Structural               O          O
    formula             CH3O "          "
                            \"          "
                             P-S-CH2CH2-S-CH2CH3
                            /           "
                       CH3O             O

    Empirical           C6H15O5PS2
    formula:

    Appearance and      White to pale yellowish, microcrystalline;
    odour:              practically odourless

    Molecular           262.29
    weight:

    Boiling point:      120°C at 0.03 mm Hg
                        144°C at 0.12 mm Hg

    Vapour              0.5 × 10-3 mm Hg at 20°C
    pressure:           1.6 × 10-5 mm Hg at 30°C
                        4.5 × 10-5 mm Hg at 40°C

    Volatility:         0.072 mg/m3 at 20°C
                        0.22 mg/m3 at 30°C
                        0.60 mg/m3 at 40°C

    Specific            1.416 at 20°C
    gravity:                     

    Solubility:         Miscible with water; soluble in most organic
                        solvents

    Minimum             94%
    purity:

    Impurities:         Oxydemeton-methyl                 max. 1.0%
                        Demeton-S-methyl                  max. 0.6%
                        O,O,S-trimethylthiophosphate      max. 1.0%
                        "thiosulphoneacid" C2H5SO2C2H4-SO2SC2H4SO2C2H5
                                                          max. 0.4%
                        Oligomeric alkyl(thio)phosphates  max. 1.0%
                                                          altogether
                        Various ionic components and      max. 1.0%
                        traces ethylenechloride           altogether
                        Water                             max. 1.0%

    Metabolism

         The metabolism of demeton-methyl in mammals has not been
    investigated but the metabolism of the homologous diethyl esters have
    been studied (see Disulfoton Working Paper). Results obtained in
    studies with both compounds on plants seemingly justify analogously
    extrapolating the results of animals experiments with demeton to
    demeton-methyl.

         With respect to demeton and its related compounds, it is known
    that the thiono compound is very readily converted to the thiol form
    (Fukuto and Metcalf, 1954). The rearrangement, particularly in polar
    solvents, takes place at a taster rate for demeton-methyl than for
    demeton. The required time in days for a 10% rearrangement in vitro
    are as follows:

                                                      
                                    O
                                  //
         Days required for P=S to P conversion at:
                            \      \
                             O      S
                                                      
                             20°C      30°C      40°C

         Demeton-S-methyl    104       26        8
         Demeton             1 460     320       91
                                                      
         (Henglein and Schrader, 1955)

         All studies undertaken with demeton revealed that the biochemical
    mechanisms in mice, insects and plants were similar (March et al.,
    1955). Major differences involved were concerned with rates of
    metabolism and degradation; and, as expected rates were greater in the
    mammal than in the insect and greater in the insect than in the plant.
    The routes of metabolism and the metabolites formed were the same in
    each case (oxidation of thioether of both isomers to the sulfoxide and
    the sulfone). Although this mechanism has not been worked out for the
    demeton-methyl family of compounds it is reasonable to assume that
    metabolism will be analogous to that observed previously with the
    demeton group.

    Effects on enzymes and other biochemical parameters

         Data are available on the cholinesterase inhibiting properties of
    thiometon. In addition, based upon analogous work with disulfoton,
    thiometon is a poor inhibitor of cholinesterase activity and when it
    is converted to the phosphorothiolate, activity of cholinesterase will
    be rapidly depressed. In one study, oxidation of demeton-S-methyl to
    the sulfoxide and sulfone did not significantly increase the
    inhibitory power. The I50 values for sheep erythrocyte cholinesterase
    were 6.5 × 10-5, 4.1 × 10-5, and 2.3 × 10-5 M. for the sulfide,
    sulfoxide and sulfone respectively (Heath and Vandekar, 1957).

         In contrast, Wirth (1958) observed that demeton-S-methyl was a
    more significant inhibitor of human blood serum cholinesterase. 150
    values reported for demeton-S-methyl, oxydemeton-methyl and
    demeton-S-sulfone were 1.65 x 10-6, 2.7 x 10-5, 4.3 x 10-5 M.
    respectively.

         Values of 4.66 and 5.10 (pI50) were recorded for thiometon with
    RBC and serum cholinesterase respectively (Kimmerle and Lorke, 1968).

         In vitro inhibition of cholinesterase was summarized in 1967
    (FAO/WHO, 1968). It was suggested that demeton-S-methyl and
    demeton-S-methyl sulfoxide (oxydemeton methyl) were essentially equal
    in cholinesterase inhibiting properties with regard to sheep RBC
    cholinesterase with an I50 value of 6.5 × 10-5 M. and 4.1 × 10-5 M.
    respectively. Klimmer (1960) reported a substantial difference in rat,
    brain cholinesterase inhibition between demeton-S-methyl and
    oxydemeton-methyl with the 150 values being 9.52 × 10-5 M. and 1.43 ×
    10-3 M. indicating that demeton-S-methyl is a more significant
    inhibitor of cholinesterase in rat brain and following thioether
    oxidation to demeton-S-methyl sulfoxide, cholinesterase depression is
    significantly reduced. Owing to the pseudo unimolecular reaction
    kinetics between organophosphates and cholinesterases. the
    determinations of these values are rarely accurate. Furthermore, such
    data given by different authors are not comparable in most instances,
    since they depend on the time of incubation.

         Subacute feeding studies were performed on rats with
    demeton-S-methyl sulfoxide and demeton-S-methyl sulfone for the
    purpose of comparing depression of cholinesterase activity. In a
    preliminary study demeton-S-methyl sulfoxide was fed 50 ppm and the
    demeton-S-sulfone was fed at 25 ppm for eight days. Both dietary
    concentrations caused approximately the same degree of cholinesterase
    activity depression in plasma and erythrocytes after four days of
    feeding: the amount of inhibition was found to have increased still
    more after eight days. In the main study, demeton-S-methyl sulfoxide
    was fed at 50 and 100 ppm and demeton-S-methyl suffers was fed at 25
    and 50 ppm for 21 days. In their effect on the cholinesterase activity
    of plasma, erythrocytes and brain, both compounds behaved similarly at
    the respected dietary concentrations with respect to both the time
    cause and the intensity of depression. To obtain the same degree of
    depression, demeton-S-methyl sulfone was administered at twice the
    amount required for demeton-S-methyl sulfoxide. The lowest activity
    was noted in plasma after 11-14 days and in erythrocytes after 14-18
    days (Loser, 1972).

         Liver function tests were performed at one and 24 hours and seven
    days following an acute oral administration of 25 mg/kg of
    demeton-S-methyl sulfone to rabbits. The Bromophthalein test and SGPT,
    and SDH activity were not affected. As would be expected,
    demeton-S-methyl sulfone is a cholinesterase inhibitor. Tests in rats
    at a dose of 11.25 mg/kg and above resulted in approximately 50%
    inhibition measured at three hours which maintained its inhibition
    level through to three days following initial treatment (Kimmerle,
    1966c).

         Following oral administration of demeton-S-methyl and the
    sulfoxide and sulfone, typical anticholinesterase symptoms were
    observed. The durations of signs of poisoning were markedly longer
    than after i.v. injection. Intravenous administration of these
    compounds (except for the demeton-O-methyl) produced typical signs of
    anticholinesterase poisoning in rats at doses close to the LD50. The

    thionate (demeton-S-methyl), however, produced immediate
    incoordination followed by accelerated respiration and weakness
    lasting several hours. Lethal amounts of the thionate produced deep
    anaesthesia with occasional jerking which lasted about 30 minutes.
    Respiration then became more rapid until the animal died within one to
    two hours. At no stage were typical anticholinesterase signs of
    poisoning observed. A similar but weaker anaesthetic stage was
    observed in rats injected IV with the thionate (demeton-S-methyl)
    isomer. Signs of poisoning were of longer duration following oral
    administration indicating a slower absorption from the gut (Heath and
    Vandekar, 1957).

    TOXICOLOGICAL STUDIES

    
    Acute toxicity

                                                                                                          
    Substance           Animal       Sex     Route        LD50 (mg/kg)    Reference
                                                                                                          

    Demeton-S-methyl    Rat          M & F   Oral         35-85           Den-Dyke, Sanderson and
                                                                          Noakes, 1970; Dubois and
                                                                          Doull, 1955; DuBois and
                                                                          Plzak, 1962; Heath and
                                                                          Vandekar, 1957; Hecht,
                                                                          1955; Kimmerle, 1966c; Kimmerle
                                                                          1972; Klimmer, 1964;
                                                                          Klimmer and Pfaff, 1955;
                                                                          Writh, 1958; Klimmer, 1961

                        Guinea-Pig   M       Oral         110             DuBois and Doull, 1955;
                                                                          Dubois and Plzak, 1962

                        Rabbit               Oral         ca. 20-50       Hecht, 1955

                        Cat                  Oral         ca 5-10         Hecht, 1955

                        Dog                  Oral         ca. 50          Hecht, 1955

                        Rat          M & F   i.p.         2-10 (techn.)   Dubois and Doull, 1955;
                                                                          Dubois and Plzak, 1962;
                                                                          Hecht, 1955; Niessen et
                                                                          al., 1963
                                                          27.5 (pure)     Niessen et al., 1963


                        Guinea-pig           i.p.         12.5            Dubois and Plzak, 1962

    Acute toxicity (cont'd.)

                                                                                                          
    Substance           Animal       Sex     Route        LD50 (mg/kg)    Reference
                                                                                                          

                        Rat          M       i.v.         8.4             Niessen et al. 1963;
                                                          17.3 (pure)     Nissen et al. 1963

                        Rat          F       i.v.         64.6 (pure?)    Heath and Vandekar, 1957

                        Mouse                i.v.         0.5-1.0         Hecht, 1955
                                                          6.8 (pure)      Hecht, 1960
                                                          8.2 (techn.)    Hecht, 1960
                        Mouse        M       i.v.         4.1 (techn.)    Niessen et al., 1963
                                                          13.0 (pure)     Niessen et al., 1963

                        Rat                  dermal       50-100          Ben-Dyke, Sanderson and 
                                                                          Noakes, 1970; Dubois,
                                                                          1960; Klotzsche, 1964

                        Cat                  dermal       10-20           Hecht,1955

    Oxydemeton-methyl   Rat          M & F   Oral         30-85           Ben-Dyke, Sanderson and
                                                                          Noakes, 1970; Dubois,
                                                                          1955; DuBois and PIzak,
                                                                          1962; Gaines, 1969;
                                                                          Heath and Vandekar, 1957; 
                                                                          Hecht, 1955; Kimmerle,
                                                                          1966c; Klimmer, 1960;
                                                                          and Wirth, 1958

                        Guinea-pig           Oral         120             DuBois, 1955; DuBois and
                                                                          Plsak, 1962

                        Rabbit               Oral         50-75           Hecht, 1955

                        Cat                  Oral         20-50           Hecht, 1955

                        Dog                  Oral         20-50           Hecht, 1955

                        Chickens             Oral         35.0            DuBois, 1962b

                        Hens                 Oral         ca. 100 ml.     Kimmerle, 1961

                        Rat          M & F   i.p.         5.82-50         DuBois, 1955; DuBois and
                                                                          Plzak, 1962; Hecht, 1955;
                                                                          Klimmer, 1960

                        Mouse                i.v.         8-12            DuBois and Plzak, 1962

    Acute toxicity (cont'd.)

                                                                                                          
    Substance           Animal       Sex     Route        LD50 (mg/kg)    Reference
                                                                                                          

                        Guinea-pig           i.p.         30              DuBois and and Plzak, 1982

                        Rat                  i.v.         47.2            Heath and Vandekar, 1957

                        Mouse                i.v.         7.5-10          Hecht, 1955

                        Rat          M & F   Dermal       100-250         Ben.Dyke, Sanders and
                                                                          Noakes; 1970; DeBois,
                                                                          1960; Dubois and Plzak,
                                                                          1962; Gaines, 1969; Hecht,
                                                                          1955; Klimmer, 1960; 
                                                                          Klotzche, 1964

                        Cat                  Dermal       >100 ccm.       Hecht, 1955

                        Rat          M       Inhalation   >1.32 mg/l      Kimmerle and Lorke, 1968
                                                          1 h exposure
                                                          0.35 mg/l
                                                          4 h exposure

    Dameton-S-methyl    Rat          M & F   Oral         32.4-30         DuBois and Doull, 1955;
    sulfone                                                               DuBois and Plzak, 1962;
                                                                          Heath and Vandekar, 1957;
                                                                          Hecht, 1955; Kimmerle, 
                                                                          1966c; Wirth, 1958

                        Mouse                Oral         28.6            Kimmerle, 1966c

                        Guinea-pig           Oral         258.0           Kimmerle, 1966c

                        Guinea-pig           Oral         120.0           DuBois and Doull, 1955;


                        Rabbit               Oral         40.0-50.0       Hecht, 1955; Kimmerle,
                                                                          1966c

                        Hen                  Oral         ca. 150         Kimmerle, 1966c

                        Cat                  Oral         25.0-50.0       Hecht, 1955; Kimmerle, 1966c

                        Dog                  Oral         >30            Hecht, 1955; Kimmerle, 1966c

                        Rat          M & F   i.p.         17.5-25         DuBois and Doull, 1955;
                                                                          DuBois and Plzak, 1962;
                                                                          Hecht, 1955; Kimmerle, 1966c

    Acute toxicity (cont'd.)

                                                                                                          
    Substance           Animal       Sex     Route        LD50 (mg/kg)    Reference
                                                                                                          

                        Guinea-pig           i.p.         85              Kimmerle, 1966c



                        Hen                  i.p.         37.5-50         Kimmerle, 1966c

                        Rat          M       i.v.         23.7            Heath and Vandekar, 1957

                        Rat          F       i.v.         21.7            Heath and Vandekar, 1957

                        Mouse                i.v.         21.7-25         Hecht, 1955; Kimmerle, 1966c

                        Mouse                s.c.         21.8            Kimmerle, 1966c

                        Rat                  Dermal       > 500           Hecht, 1955; Kimmerle, 1966c

                        Cat                  Dermal       > 500           Hecht, 1955

    Demeton-O-methyl    Rat                  Oral         676             Heath and Vandekar, 1957
                                             i.v.         216             Heath and Vandekar, 1957
                                                                                                          

    
    Antidotal studies

         Atropine and PAM were found to have a protective effect in rats
    against the acute oral toxicity of oxydemeton-methyl and the sulfone.
    Although PAM and atropine alone were both therapeutic, combinations of
    both compounds did not Afford any greater protection to rats
    (Kimmerle, 1966a, 1966b, 1966c; Lorke and Kimmerle, 1968; Dubois and
    Plzak, 1962). On the other hand, atropine was not effective, either
    alone or in combination with PAM when tested against demeton-S-methyl
    (Kimmerle, 1966a; Lorke and Kimmerle, 1969; Klotzsche, 1964). Atropine
    and PAM were found to be ineffective in protecting against the acute
    toxic effects of oxydemetonmethyl in hens (Kimmerle, 1961).

    Special studies

    (a)  Demeton-S-methyl

         None available.

    (b)  Demeton-S-methyl Sulfoxide

    Special studies on dermal toxicity

         Two groups of five female rats each were administered 25 and 50
    mg/kg daily by dermal application for 60 days. No mortality occurred
    in either group over the period of time although the high dose group
    exhibited signs of cholinergic stimulation in the first two weeks of
    treatment. Continued treatment with oxydemeton-methyl to rats showed
    that after prolonged exposure the animals developed a tolerance to the
    acute signs of poisoning (DuBois, 1962a).

         Oxydemeton-methyl was administered dermally to male and female
    rats five days a week for three weeks at doses approximating one-fifth
    of the LD50. A formulation of oxydemeton-methyl (Metasystox-R)
    containing 2 lb active ingredient per gallon of formulation was used.
    The acute dermal LD50 was approximately 112.5 mg/kg (450 mg
    formulation/ kg) in both male and female rats. Male and female rats
    given daily dermal exposures to this formulation exhibited a slight
    inhibition of body weight gain and a marked inhibition of brain
    cholinesterase activity. Repeated dermal exposure did not affect body
    weight of various organs nor haematological values examined at the end
    of this period (DuBois et al., 1966).

         Histological examination of certain tissues revealed no changes
    that could be attributed to the presence of oxydemeton-methyl as a
    Metasystox-R formulation in the diet (Wren of al., 1968).

    Special studies on mutagenicity

         Groups of male mice (12 Charles River mice per group) were
    administered oxydemeton-methyl by intraperitoneal administration at
    levels of 0, 5, and 10 mg/kg. These animals were then mated with three
    untreated virgin females per week for six consecutive weeks. The
    females were sacrificed approximately one week after mating and the
    ovaries and uterus examined for early resorption. The authors indicate
    that pre-implantation losses for all groups were not affected by
    oxydemeton-methyl administration and that the material did not cause a
    "dominant-lethal" response. Data indicated that females mated to males
    treated with 10 mg/kg after six weeks had a high number of early
    resorption sites. During all other weeks the reproduction indices were
    normal (Arnold et al., 1971).

    Special studies on neurotoxicity

         Adult hens administered oxydemeton-methyl orally at doses up to
    the LD50 level showed no indications of delayed neurotoxic response
    (Kimmerle, 1961).

    Special studies on potentiation

         Studies on the acute potentiation of oxydemeton-methyl in
    combination with 15 other organophosphates and one carbamate
    anticholinesterase agents administered simultaneously at one half of
    the LD50 dose by intraperitoneal injection resulted in less than
    additive acute toxicity. No evidence of potentiation of acute toxicity
    was obtained by administration to rats of the pairs of compounds
    (DuBois, 1961). Oral administration of demeton-S-methyl to male rats
    in combination with phenamiphos (SRA-3886, 
    ethyl-4-(methylthio) m-tolyl-isopropyl-phosphoroamidate, Bay 68, 138,
    NemacurR) resulted in no potentiation of the acute toxicity
    (Kimmerle, 1972). Thiometon did not potentiate the acute toxicity of
    formothion (FAO/WHO, 1970).

    Special studies on reproduction

         In a three generation reproduction study at oxydemetonmethyl
    dietary levels of 0, 10, 25 and 50 ppm, groups of 10 males and 20
    females of each generation, except the third filial, were maintained
    through two successive matings. Second litter animals were used for
    composing the succeeding generation groups. The third filial
    generation was maintained only to weaning age. At 50 ppm in all
    generations, the number of pregnancies and the number of young per
    litter were significantly reduced. Histological examination of the
    second filial generation animals disclosed only reduced oogenesis in
    three of the 10 in the 50 ppm females, with no apparent effect at 25
    ppm. 10 ppm was without effect on the number of pregnancies, the
    number of young per litter, the number of surviving young up to 21
    days and microscopic appearance of major organs. Erythrocyte
    cholinesterase activity, expressed in percentage of controls, was
    reduced to 83% in males and 67% in females in the third filial
    generation, after 21 days; and in the second generation, after 27
    weeks, to 83% in the males and to 61% in the females. Erythrocytic
    cholinesterase activity was more consistently reduced, in proportion
    to the test level, at the two higher levels. No gross abnormalities
    nor effect on food consumption or body weight gain were seen at any
    test level (reviewed in FAO/WHO, 1968).

    Special studies on teratogenicity

         Groups of 15 pregnant rabbits were administered oxydemeton-methyl
    in doses of 0, 0.1 and 0.2 mg/kg from day 6 through day 18 of
    gestation. Negative controls were treated with empty capsules and
    positive controls were treated with 37.5 mg/kg/day of thalidomide. At
    day 29 all animals were sacrificed and young were removed by caesarean
    
    section, weighed and observed in an incubator for 24 hours. All young
    were further observed by gross examination and by alizarin staining of
    the bone.

         No deaths or unusual reactions were noted in any of the females
    nor was there any effect on weight gain that could be attributed to
    the administration of oxydemeton-methyl to the animals. Fetal
    mortality was not affected by oxydemeton-methyl and there were no
    abnormalities observed among the fetuses from the low dose group. A
    single incidence of talipes varus was observed which was believed to
    have occurred spontaneously although it was not noted in the controls
    of this test. Positive results were obtained with thalidomide
    indicating the susceptibility of the strain of animals to teratogenic
    effects. It is believed that administration of oxydemeton-methyl
    during the susceptible period of gestation does not result in
    teratogenic abnormalities in rabbits (Ladd et al., 1971).

    (c) Demeton-S-methyl sulfone

    Special studies on neurotoxicity

         Following acute oral and intraperitoneal administration to hens,
    demeton-S-methyl sulfone at levels up to and including 200 mg/kg did
    not induce any neurotoxic effect in hens (Kimmerle, 1966c).

         Demeton-S-methyl sulfone was found to be non-irritating to the
    rabbit ear following in contact for 24 hours and after a seven-day
    observation period. A small quantity of demeton-S-methyl sulfone
    placed in conjunctival sack of rabbits produced a slight reddening of
    the conjunctival but no change in the cornea. Constriction of the
    pupil was noted (Kimmerle, 1966c).

    Inhalation exposure

         Groups of rats (10 males and 10 females per group) were exposed
    for four hours daily for a period of 10 weeks (five exposures per
    week) to concentrations of 0, 0.0068 and 0.017 mg/litre. Signs of
    cholinergic stimulation were seen within two weeks at all
    concentrations tested although no deaths occurred over the course of
    this experiment. There was a significant decrease in body weight gain
    over the course of the experiment although haematology was normal.
    Urine examinations were normal as were the gross and microscopic
    examinations of tissues and organs. Cholinesterase depression was
    obvious in all groups with 50% depression being noted at the low
    concentration (Kimmerle. 1966c).

    Short-term studies

    (a) Demeton-S-methyl

    Rat. Groups of male rats (15 rats per group) wore orally
    administered demeton-S-methyl daily for up to six months at doses of
    0, 1, 5 and 10 mg/kg (Klimmer, 1961). Mortality was evident at 5 and
    10 mg/kg and was absent at the lowest treatment level. Cholinergic
    signs of poisoning evident at the beginning of the study became less
    evident as the study progressed. No effects were noted at 1 mg/kg/day
    (equivalent to administration of 10 ppm in the diet).

         Groups of six male rats were fed demeton-S-methyl in the diet for
    six months at levels of 0, 50, 100 and 200 ppm (Vandekar, 1958).
    Cholinergic signs of poisoning were evident at the highest level at
    the beginning of the study and lessened as time progressed. Depression
    of cholinesterase activity was evident at all feeding levels. Growth
    was depressed at 100 ppm. Gross and microscopic examination of tissues
    showed no change attributed to the demeton-S-methyl in the diet.

         Weanling male and female rats (Sprague-Dawley strain) Were fed
    diets containing 0, 2, 5, 10 and 20 ppm demeton-S-methyl for three
    months. Growth rate, food consumption, physical condition and
    mortality were not effected at any of the feeding levels. Measurement
    of serum and erythrocyte cholinesterase were performed at eight weeks
    and at the end of the feeding period when all animals were sacrificed
    for gross and microscopic tissue examination. There was no indication
    of toxic effects at dietary levels of 10 ppm or less (Root and Doull,
    1972).

    (b)  Demeton-S-methyl sulfoxide

    Rat. In groups of 20 rats, administration of oxydemeton methyl by
    mouth in doses of 5 ag/kg bw daily for three months caused no signs of
    intoxication or pathological changes, and 10 mg/kg bw for 21 days
    caused an inhibition of cholinesterase activity after four to six days
    (reviewed by FAO/WHO, 1968).

         Groups of six males and six females received oxydemeton-methyl
    concentrations of 20 ppm or less in the diet for a period of 16 weeks:
    no significant influence on growth-rate or food consumption was
    observed. 10 ppm or less caused no significant depression of
    erythrocyte cholinesterase activity. Gross and microscopic examination
    of the tissues of rats revealed no indication of toxic effects except
    for fatty changes in the livers of some of the rats fed 10 ppm and 20
    ppm. 50 ppm for six months had no effect on weight gains in a group of
    six rats and showed no pathological changes attributable to the action
    of the compound. The brain and blood cholinesterase activity was
    strongly inhibited. Concentrations of 100 and 200 ppm produced signs
    of intoxication in the first three weeks of the experiment (Bar, 1963;
    Vandekar, 1958; reviewed in FAO/WHO, 1968).

         A group of 20 male rats were orally administered
    oxydemeton-methyl daily five times per week for 75 days at a level of
    5 mg/kg. Behaviour was not affected although growth was depressed. A
    further study at 5 and 10 mg/kg for 21 days resulted in mortality at
    10 mg/kg within one week. Cholinergic signs of poisoning observed in
    the first week were not evident at the end of the study (Klimmer,
    1960).

         Groups of rats (six male and six female Sprague-Dawley strain
    rats per group) were fed dietary levels of oxydemetonmethyl in the
    diet at levels of 0, 2, 5, 10 and 20 ppm for a period of 16 weeks.
    Behaviour, mortality, growth rate and food consumption data were
    recorded over this 16 week period. At the conclusion of the experiment
    gross and microscopic examination of tissues and organs and
    cholinesterase determination of serum, erythrocyte, brain and
    submaxillary gland were performed. Gross pathology, including absolute
    organ weights and organ to body weight ratios was normal at all
    feeding levels. Histological changes in the livers of rats fed the two
    highest dietary concentrations consisted of vacuolization of the
    cytoplasm of the hepatic cells in the periportal region. These changes
    were apparent in some of the animals fed the control diet but were
    more pronounced in the animals fed the two highest
    oxydemeton-methyl-containing diets. The changes were less severe and
    similar to the controls in the rats fed 2 and 5 ppm. Sections of the
    liver of animals exhibiting these changes also were found to stain
    positively for the presence of fat (with oil red, 0). Growth, food
    consumption, behaviour and body weight changes were not noted during
    the course of the study. Depression of cholinesterase activity in BBC
    and brain were observed in both males and females at 20 ppm in the
    diet. Serum and submaxillary gland cholinesterase appeared to be
    unaffected in the study, although male submaxillary gland
    cholinesterase activity was slightly depressed at the highest feeding
    level.

         A no-effect level in this study appears to be 5 ppm in the diet
    based upon somatic effects noted on microscopic examination of liver
    after 16 weeks. A level of 10 ppm in the diet had no effect on
    cholinesterase activity (Doull et al., 1962).

         Groups of rats (12 male and 12 female rats per group) were fed
    diets containing oxydemeton-methyl for a period of 16 weeks at levels
    of 0, 2, 5 and 10 ppm. Cholinesterase activity was also determined at
    the end of the experiment in plasma, RBC, brain and submaxillary gland
    (Root et al., 1967a). Gross and microscopic pathology was reported on
    the following tissues: brain, liver, kidney, lymph node, spleen,
    heart, lung, gonad, thymus, adrenal gland, urinary bladder, stomach,
    duodenum, pancreas, jejunum. There was no effect on food consumption,
    growth or survival in any of the levels examined. Haematology and
    clinical chemistry were not affected although male rats receiving 10
    ppm showed a slight decrease in blood glucose. Cholinesterase
    depression measured at the conclusion of the study showed depression
    of plasma cholinesterase at 10 ppm in both males and females.

    Erythrocyte, brain and submaxillary gland inhibition cholinesterase
    inhibition at 5 ppm in both males and females. A dietary level of 2
    ppm was observed to be a no-effect level on cholinesterase. Gross and
    histologic examination of the tissues of male and female rats
    containing levels up to 10 ppm Metasystox-R for 16 weeks showed no
    differences from the controls (Root et al,, 1967a; Hibbs and Nelson,
    1967). in a separate study, groups of rats (12 males and 12 females
    per group) were fed 0 and 20 ppm oxydemeton-methyl for 16 weeks (Root
    and Meskauskas, 1968). Gross and microscopic analysis of the liver
    showed no effects attributable to oxydemeton-methyl in the diet.

         Groups of rats (12 male and 12 female) were fed oxydemeton-methyl
    in the diet for 13 weeks at dietary concentrations of 0, 1, 1.5, 2,
    30, 50 and 100 ppm.

         Growth in animals fed 2 ppm and below was not affected by the
    presence of oxydemeton-methyl in the diet. Food consumption was
    reduced at 100 ppm and growth was reduced at 30 ppm and above. There
    was no apparent mortality resulting from the incorporation of
    oxydemeton-methyl in the diet. There was no effect on haematology and
    blood chemistry and gross pathology was affected only at 100 ppm in
    the diet. At this high level, organ weights were generally reduced
    with the exception of the brain which was apparently unaffected., At
    dietary levels of 1.5 ppm and above erythrocyte cholinesterase was
    depressed slightly while plasma, brain and submaxillary gland
    cholinesterase was depressed only at levels of 30 ppm and above.

         There were no histological findings that could be attributed to
    the presence of oxydemeton-methyl in the diet at levels up to and
    including 100 ppm. A no-effect level in this study based upon
    depression of cholinesterase was 1.0 ppm (Root of al., 1968; Wren and
    Nelson, 1969).

         Groups of rats (WISTAR strain SPF rats, 15 male and 15 female per
    treatment group; 30 male and 30 female rats per control group) were
    fed dietary concentrations of oxydemetonmethyl of 0, 1, 3, 25 and 125
    ppm in the diet for 90 days.

         Signs of cholinergic stimulation appeared within three weeks at
    the 125 ppm dose level, continued to increase in severity after the
    onset of the experiment, and gradually diminished. Food consumption
    was low in the highest test group and this was reflected in the
    reduced growth curve for both male and female which was significantly
    depressed at this high feeding level. There was a slight increase in
    mortality at the high dose level in males although the females
    survived the entire test. There were no significant effects at levels
    up to and including 125 ppm in the diet on clinical chemistry,
    haematology, urinalysis, kidney function tests, blood, sugar or
    cholesterol. Plasma cholinesterase was significantly depressed at 25
    ppm in both males and females. Erythrocyte cholinesterase was
    depressed in both males and females at 5 ppm in the diet. Gross
    histological examination indicated a significantly lower organ weight

    in several tissues (heart, lung, liver, spleen, kidney, adrenals, and
    gonads in males and heart, thyroid and spleen of females at 125 ppm in
    the diet). In females, the reduced organ weights when compared with
    the reduced body weight resulted in a normal organ to body weight
    ratio. In other tissues such as thymus, lung, liver, and kidneys the
    size of which were not reduced the reduced body weight caused the
    calculation to reflect an increased organ to body weight ratio. No
    histological change was seen in the tissues examined which could be
    attributed to the presence of oxydemeton-methyl in the diet (Vince and
    Spicer, 1971). A no-effect level in this study was 1 ppm.

         Groups of weanling rats (six rats per group) were fed
    oxydemeton-methyl in the diet at levels of 0, 1, 5 and 25 ppm for
    seven days. At the end of one week the animals were sacrificed for the
    measurement of the hydrolysis of tributyrin and diethyl succinate
    (DES) by liver and serum and for the measurement of cholinesterase in
    serum, liver, and brain. Dietary levels of oxydemeton-methyl producing
    50% inhibition of aliesterase and cholinesterase over this one week
    feeding period were obtained by analysis of a plot of the logarithm of
    dietary concentration and inhibition of the respective enzymes.
    Dietary level producing 50% inhibition of brain, liver, and serum
    cholinesterase was 15, 28 and 20.5 ppm, respectively. Dietary level to
    induce 50% inhibition of DES hydrolysis in liver and serum was 6.1 and
    24.0 ppm respectively and for tributyrin hydrolysis in liver and serum
    the values were 4.2 and >25 ppm respectively (Su et al., 1971).

    Dog. Diets containing 0, 5, 10 and 20 ppm oxydemeton-methyl have
    been fed to male and female beagle dogs for periods of 12 weeks. None
    of these dose levels produced significant changes in food consumption
    or body weight or gave rise to cholinergic signs. Levels of 10 ppm or
    less did not cause significant inhibition of serum or erythrocyte
    cholinesterase activity (Root et al., 1963; reviewed by FAO/WHO, 1965
    as oxydemeton-methyl).

         Groups of dogs (one male and one female per group) were fed
    dietary levels of oxydemeton-methyl in the diet at levels of 0, 5, 10
    and 20 ppm for 12 weeks. There was no change in food consumption or
    body weight over the treatment period. Serum cholinesterase was
    depressed at 20 ppm within one week to approximately 80% of normal and
    remained at this level for the remainder of the study. Red blood cell
    cholinesterase was continuously depressed from the beginning of the
    study at 20 ppm in the diet and reached approximately a 30% inhibition
    level after the 12-week period. In this study, the level of 20 ppm
    reflected a minimal effect in cholinesterase of red blood cell in dogs
    (Root et al., 1963).

         Male and female beagle dogs were fed diets containing 0, 2, 5,
    10, and 20 ppm demeton-S-methyl sulfoxide for three months.
    Observations on growth rate, food consumption, physical activity and
    mortality indicated no effects at any of the feeding levels.
    Measurement of serum and erythrocyte cholinesterase were made weekly
    in the dogs and it was found that no toxic effects in the animals at

    levels of 10 ppm or less was observed. There was no effect on food
    consumption, growth or survival over the 12-week feeding period. Male
    and female dogs at 10 ppm showed a slight increase in SGPT activity
    with no other effect noted on the haematological examination. There
    appeared to be no significant somatic effects noted on gross or
    histological examination. Plasma cholinesterase was unaffected at all
    feeding levels while RBC brain and liver (especially in females)
    cholinesterase was depressed significantly at 10 ppm in the diet. The
    only apparent effect of oxydemeton in dogs is a slight RBC
    cholinesterase depression and a more substantial decrease in esterases
    activity of female brain and liver (Root et al., 1967; Root, 1969;
    Root and Doull, 1972).

         Two groups of four male and four female dogs were fed
    oxydemeton-methyl in the diet for 12 weeks. One group was maintained
    as a control and the second group of dogs was fed a dietary level of
    50 ppm for three weeks, 75 ppm for three weeks, and 150 ppm for the
    final six weeks. At a dietary level of 50 ppm for three weeks no gross
    detectable cholinergic signs of poisoning were evident. The level when
    raised to 75 ppm resulted in no overt signs of toxicity. However, upon
    introduction of 150 ppm oxydemeton-methyl to the diet, severe signs of
    cholinergic stimulation were evident resulting in death of one of the
    four dogs. At the conclusion of the study, it was observed that at 150
    ppm there was a significant and uniform reduction of liver
    cholinesterase as well as brain cholinesterase in both sexes. Plasma
    cholinesterase was depressed within the first week of the experiment
    (at 50 ppm) to about 46% of normal at which level it remained
    relatively constant for the entire feeding study. Erythrocyte
    cholinesterase was continuously depressed at 50 ppm for the entire
    three-week period of feeding after which it stabilized at a level
    somewhat below 20% and was maintained at this level for the entire
    duration of the experiment. Haematological values were slightly
    altered in males by the presence of oxydemeton-methyl with the
    clotting time being reduced and the SGPT activity being increased,
    Similar effects were not noted in females on these two parameters. No
    other clinical observations were observed to be abnormal. Gross
    examination of various tissues and organs at the conclusion of the
    study showed a decrease in spleen weight in both males and females; a
    substantial increase in male thymus; a decrease in female thymus; an
    increase in the thyroid gland in males and a decrease in females.
    Microscopic examination of tissues of these animals showed no
    significant changes, which could be attributed to the presence of
    oxydemeton-methyl in the diet (Root et al., 1970; Wren, 1970).

         Groups of dogs (four male and four female per group) were fed
    oxydemeton-methyl for two years at dietary levels which varied from
    0.5 to 150 ppm in the diet. Groups of four male and four female dogs
    were fed a normal dry diet for this same period of time. The dietary
    feedings levels were varied in all three groups of treatments with a
    low level initiated at 0.5 ppm and fed for 29 weeks after which the
    diet was switched to 1.0 ppm for weeks 30-43, and was increased to 2
    ppm during weeks 43-77 after which it was raised to 4 ppm for weeks

    7883 and then reduced to 2 ppm for the remainder of the study. The
    level of 5 ppm in the diet was fed to the intermediate group for the
    first 28 weeks after which it was raised to 10 ppm and the animals
    maintained on this diet for the remainder of the two-year study. The
    third group of animals (the highest dosed group) received 37.5 ppm for
    the first 28 weeks after which the level was raised to 75 ppm for
    weeks 29-77; 100 ppm for weeks 78-79; 125 ppm for weeks 80-83; 150 ppm
    for weeks 84-88; and 100 ppm for weeks 89-104. There was no effect
    over the two-year period on growth or food consumption. Behaviour of
    animals at the highest dose level was abnormal at 125 ppm with signs
    of poisoning being evident during the short period of time which they
    were fed at this level and higher. There was no apparent signs of
    cholinergic stimulation at 100 ppm. Haematological values, urinalysis
    and clinical chemistry were all normal. No abnormalities were noted
    with respect to organ weight data or organ to body weight or brain
    weight ratios in all the test groups. There were no effects noted when
    tissues of the animals were examined histologically.

         Cholinesterase from various tissue sources was significantly
    depressed in several of the groups over the period of this study.
    Brain cholinesterase was significantly depressed in the highest group
    while depression was not noted in the intermediate groups at levels up
    to 10 ppm in the diet. Plasma cholinesterase was also inhibited in the
    highest group and depressed in the intermediate group especially at
    52 weeks and thereafter in the males. There was also a slight
    depression noted in the females at this time period. There was no
    apparent depression in either males or females at the 39-week interval
    which might have been indicative of a dietary switch from 5 to 10 ppm
    which took place in week 28. As week 39 was essentially normal, the
    slightly depressed values noted in the 10 ppm level may not reflect a
    true inhibition of plasma cholinesterase. At the lowest level fed
    there was a slight depression especially in females at the 52, 78 and
    104 weeks although again not coinciding with any dietary change. Red
    blood cholinesterase was depressed in the highest group and was also
    depressed in the intermediate group especially in males, at all
    intervals tested. In females, depression was noted only at week 39 and
    at each interval thereafter. There appear to be a significant drop at
    both male and female BBC cholinesterase values, at week 39 which would
    correspond to the change from 5 to 10 ppm in the diet. At the lowest
    dose level there is a slight depression noted only at 104 weeks in
    both males and females. This is presumably a reflection of the change
    in dietary concentration to 4 ppm which took place at week 78. The
    possibility exists that the effect of this concentration change would
    be reflected only at week 104. 2 ppm is considered a no-effect level
    in dog (Hartke et al., 1973).

    (c) Demeton-S-methyl sulfone

    Rat. Groups of rats (six male and six female WISTAR strain rats per
    group) were orally administered demeton-S-methyl sulfone five days per
    week for 10 weeks at dosage levels of 0, 1.3, 2.5, 5.0, 9.5 and 19
    mg/kg. Behaviour and mortality were observed daily and growth and food

    consumption were examined weekly. Mortality was observed at the two
    highest dose levels with typical signs of cholinesterase depression
    and cholinergic stimulation. In females, levels of 2.5 mg/kg and above
    resulted in a reduction in growth while in males only the 5.0 mg/kg
    were so reduced. There was no effect on the haematological values and
    urine examination for protein, sugar, and sediment showed no
    differences from the controls. Cholinesterase depression was obvious
    at all feeding levels with the level of 1.3 mg/kg resulting in
    approximately 50% depression. Over the course of the study, the enzyme
    depression appeared to be maintained for five weeks after which there
    was a further drop in activity which subsequently recovered to values
    approximately 75% of normal. There was no effect on gross and
    microscopic pathology in this study (Kimmerle, 1966c).

         Groups of rats (14 males and 14 females per group) were fed
    demeton-S-methyl sulfone in the diet at concentrations of 0, 2.5, 10
    and 40 ppm for four to six months. Growth was recorded bi-weekly and
    at the conclusion of the study cholinesterase activity in brain, RBC
    and plasma were determined. No clinical signs of poisoning were
    observed over the period of this study and food consumption and weight
    gain were comparable to the controls. There was no apparent effect on
    gross pathology as observed at the end of the feeding period and
    cholinesterase depression in all tissues was obvious brain, plasma and
    erythrocyte at 10 ppm. 2.5 ppm was judged to be a no-effect level in
    this study (Klimmer, 1965).

         Groups of rats (15 male and 15 female WISTAR rats per group, 30
    male and 30 female rats were the control group) were fed
    demeton-S-methyl sulfone in the diet at concentrations of 0, 1, 3, 10
    and 30 ppm for three months.

         Behavioural changes were observed in the animals fed 30 ppm in
    the diet at the beginning of the experiment. These signs of poisoning
    were reduced-as the experiment progressed. Food consumption in the
    animals receiving 30 ppm was reduced as was the growth of males. At 10
    ppm and below there was no effect on growth and mortality. There was
    no apparent effect of demeton-S-methyl sulfone on clinical chemistry,
    haematological values, urinalysis and kidney function tests.
    Cholinesterase activity in plasma and erythrocyte was measured at 2,
    4, 8 and 13 weeks and was observed to be inhibited at both 10 and 30
    ppm in both sexes and marginally was depressed at 3 ppm and above in
    both sexes. 1 ppm showed no effect on cholinesterase activity. Gross
    examination of tissues and organs showed no indication of adverse
    effect due to the compound in the diet. The no-effect level in this
    experiment was 1 ppm in the diet based upon cholinesterase depression
    (Loser, 1971b). Histological examination of the following tissues
    showed no somatic effects of the compound (Newman and Urwin, 1972).

    Long-term studies

    (a)  Demeton-S-methyl

         None available.

    (b)  Demeton-S-methyl sulfoxide

    Rat. Groups of Charles River rats (35 males and 35 females per
    group) were fed oxydemeton-methyl in the diet for 22 months at dose
    levels which varied in the experimental design from 0 to 100 ppm. The
    low dose group received 0.5 ppm for six months followed by 1 ppm for
    three months, 2 ppm for eight months, 4 ppm for one month, and 2 ppm
    for the two final months. The intermediate group received 5 ppm for
    six months then 10 ppm for the remainder of the experiment. The high
    dose group received 25 ppm for one month, 37.5 ppm for the second
    month, 50 ppm for the next four months, 75 ppm for the next three
    months, and then 100 ppm for the remainder of the study. Growth and
    body weight was affected especially in males. Over the entire course
    of the study growth in females was not significantly affected. Over
    the course of the first six months, growth was depressed in males at
    0.5 and 5 ppm in the diet and in the highest group which varied from
    25 to 50 PPM. At six months, weight gain was depressed with the
    controls gaining 427 g, the 0.5 ppm gaining 364 g, the 5 ppm gaining
    350 g and the high group 309 g over this period. Data for females were
    all similar to the controls. A comparison of the gain in weight over
    months 10 to 17 where 2 ppm (the lowest group) was added to the diet
    show the controls to have gained 104 g while the 2 ppm males gained
    only 8 g. A plot of the average body weight data showed that there
    were definitive effects on males at the lowest concentration in the
    diet. At the conclusion of the 22-month study the total weight gain
    data showed females to be unaffected while males appeared to be
    significantly affected at the highest level and moderately affected at
    the other two levels tested.

         Haematological and urinalysis were normal and mortality over the
    course of the study was not related to the oxydemeton in the diet.
    Serum and alkaline phosphatase (SAP) activity in the high dose group,
    the only group examined, was elevated sporadically principally in
    females but does not appear to be related to the administration of
    oxydemeton. No other clinical chemistry parameter was abnormal.

         Cholinesterase depression was significant at the higher level in
    both sexes in plasma, RBC, and brain tissues. At the intermediate
    level, cholinesterase was significantly depressed again in the RBC and
    brain and depression was observed in the plasma only at the conclusion
    of the study. Cholinesterase was unaffected at the lower group level
    in all tissues over the course of the whole study.

         No differences were noted between the test and the control
    animals on gross pathological examination. Kidney, liver and spleen
    weights were decreased in males. Weight of the liver in males was

    significantly reduced at the two highest feeding levels. The organ to
    body weight ratios were unaffected although the organ to brain weight
    ratios in the two highest groups were significantly reduced. In the
    kidneys of males, the absolute organ weight was depressed at all
    feeding levels as was the organ to brain weight ratio but not the
    organ to body weight ratio. A reduced spleen weight of the male
    animals on the highest and the lowest but not the intermediate level
    was observed. Organ to body weight ratios were unaffected but organ to
    brain weight ratios were similarly reduced. Gross effects were not
    observed with any other tissues. Histopathological examination of all
    tissues and organs showed no differences from the control. A no-effect
    level of 2 ppm in the diet based on cholinesterase depression was
    observed (Reyna et al., 1973),

    (c)  Demeton-S-methyl sulfone

         None available.

    Observations in man

         In studies on volunteer subjects, the no-effect level determined
    for oxydemeton-methyl after a 60-day period of administration was 0.05
    mg/kg bw. An 0.4 mg/kg level caused depression of serum and
    erythrocyte cholinesterase activity after a short time but no signs of
    poisoning were seen. A single application of 1 mg/kg is tolerated
    without affecting cholinesterase activity whereas 2 mg/kg inhibits the
    enzyme (Doull, 1973).

    Comments

         Demeton-S-methyl and related compounds including
    demeton-S-methyl sulfoxide (oxydemeton-methyl) and demeton-S-methyl
    sulfone are alkylthioether dimethyl organophosphate esters
    structurally analogous to demeton, the diethyl ester, and are
    absorbed, distributed and metabolized in the same way as demeton in
    various biological systems. The metabolism of these compounds, by
    analogy with the diethyl esters, would result in oxidation of the
    thioether to the sulfoxide and the sulfone. It has been suggested
    that the sulfoxide, the major terminal residue in plants, is
    responsible for the toxicological effects, Toxicological data
    indicate that oxydemeton-methyl is not teratogenic to rabbits, not
    mutagenic to mice and does not interfere with reproduction in rats.
    None of these compounds induce delayed neurotoxic signs of poisoning
    in hens nor do they potentiate the acute toxicity of other
    anticholinesterase organophosphate or carbamate insecticides. The
    thioether is the most active in vitro anticholinesterase agent
    with the sulfoxide and the sulfone being less active. Short-term
    studies with demeton-S-methyl in rat and dog resulted in a no-effect
    level of 10 ppm in both species based on cholinesterase depression.
    Similar studies with the sulfone indicate a marginal
    anticholinesterase effect at 3 ppm with no effect noted at 1 ppm.

    Short-term studies with demeton-S-methyl sulfoxide and two-year
    studies in rats and dogs indicate a no-effect level of 2 ppm based
    on cholinesterase depression in both species. Fatty degeneration
    was seen in the liver but only in response to exposure at high dose
    levels. A close of 0.05 mg/kg/day over a 60-day period was tolerated
    in man with no evidence of cholinesterase depression. An ADI was
    established on the basis of the long-term studies in animals and
    observations in man.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat:      2 ppm in the diet equivalent to 0.1 mg/kg bw

         Dog:      2 ppm in the diet equivalent to 0.05 mg/kg bw

         Man:      0.05 mg/kg per-day

    Estimate of acceptable daily intake for man

         0-0.005 mg/kg*

              
    *  The total demeton-S-methyl, demeton-S methyl sulfoxide and
       demeton-S-methyl sulfone should not exceed this figure.

    RESIDUES IN FOOD AND THEIR EVALUATION

         The three compounds are systemic insecticides used for the
    control of aphids, scales, spider mites, sawflies, leafhoppers and
    thrips. They are used in numerous crops, particularly cotton,
    vegetables, potatoes, cereals, tobacco, hops and fruit.
    Demeton-S-methyl and oxydemeton-methyl are marketed as emulsifiable
    concentrate formulations in many countries of Europe, Asia, America,
    Africa and Australia.

         Demeton-S-methyl sulfone is marketed only in combination with
    azinphos-methyl as a wettable powder formulation, practically only in
    European countries.

         Demeton-S-methyl products are registered in 31 countries,
    oxydemeton-methyl products in 86 countries, and demeton-S-methyl
    sulfone in 13 countries.

         The usage on different crops is as follows:
                                                                          
                             Demeton-S-        Oxydemeton-   Demeton-S-
                             methyl            methyl        methylsulfone
                                                                          
         Field Crop          55%               45%           -

         Vegetables          35%               40%           10%
         including
         potatoes

         Fruit Crops         10%               15%           90%
         including grapes
         and citrus fruit
                                                                          

    Pre-harvest treatment

         Demeton-S-methyl and oxydemeton--methyl are usually applied in
    concentration 0.025% a.i. and demeton-S-methyl sulfone as 0.015% a.i.
    Depending on crops, the pesticides are applied one to five times in a
    season. Recommended rates of application and safety intervals for
    different crops are as follows.

                                                                     
                                  Application rate         Pre-harvest
    Crop                          (a.i.)                   interval
                                                                     

    Demeton-S-methyl

    Fruit                         500 g/ha                 21 days
    Vegetables                    150-250 g/ha             14-21 days
    Field crops generally         150-300 g/ha             21 days
    Cotton                        500 g/ha                 14 days

    Demeton-S-methyl

    Sugar cane                    200-400 g/ha             14 days
    Maize                         400-600 g/ha             14 days

    Oxydemeton-methyl

    Fruit                         300-500 g/ha             21 days
    Vegetables                    150-600 g/ha             14-21 days
    Field crops                   150-600 g/ha             14-21 days

    Demeton-S-methyl sulfone

    Fruit                         300 g/ha                 21 days
    Vegetables                    100 g/ha                 14-21 days
                                                                     

    Post-harvest treatments

         No recommended uses.

    Other uses

         All three compounds are recommended for the control of pest on
    ornamentals.

    Residues resulting from supervised trials

         In biological systems, conversion constantly takes place
    according to the following scheme:

         demeton-S-methyl --> oxydemeton-methyl -->
         demeton-S-methyl sulfone

         Therefore, methods for the analysis of residues must determine
    the following compounds:

    after application of demeton-S-methyl:  demeton-S-methyl + 
                                            oxydemeton-methyl + 
                                            demeton-S-methyl sulfone

    after application of oxydemeton-methyl: oxydemeton-s-methyl sulfone +
                                            demeton-S-methyl sulfone

    after application of demeton-S-methyl sulfone:    demeton-S-methyl
                                                      sulfone.

         Residue data are available from supervised trials carried out in
    different countries on food crops grown under various conditions. In
    most cases normal dosage rates were applied in accordance with label
    instructions. However, in some experiments higher dosages were also
    included.

         The data of the trials are summarized in Table 1. Those trials
    carried out before the introduction of GLC wore analysed by the total
    phosphorus method.

    TABLE 1. TYPICAL RESIDUE RANGES RESULTING FROM RECOMMENDED APPLICATION
             RATES AND FREQUENCIES OF APPLICATION OF DEMETON-S-METHYL,
             OXYDEMETON-METHYL, AND DEMETON-METHYL SULFONE

                                                                      
                             Pre-harvest   Residue        Country/
    Crop                     interval      (ppm)          number
                                                          of trials
                                                                      

    Apples                   14-28         n.d. - 1.3     GFR, USA/18
    Pears                    14-28         n.d. - 0.1     USA/7
                                           0.2 - 0.6      GFR/1
    Peaches                  14-28         - 0.2          GFR/1
                                           n.d. - 0.7     USA/3
                             14-21         0.5 -2.3       S.Afr/1
    Plums                    14-28         n.d. - 0.75    GFR, USA/4
    Strawberries             14-28         n.d. - 0.6     USA/7
    Blackcurrants            14-28         0.16 - 0.63    GFR/2
                             14            4.0            UK/1
    Redcurrants              14-28         1.0 - 1.3      USA/2
    Raspberries              14-28         0.1 - 0.6      USA/1
    Grapes                   14-28         0.05 - 2.7     USA/8
                                           0.23 - 0.5     GFR/7
    Citrus fruits            14-28         n.d. - 0.5     USA/9
      (whole fruit)
    Brassicas (cabbage,      21            n.d. - 0.45    GFR.S.Afr.
      brussell sprouts,                                   USA/26
      cauliflower,
      broccoli)
    Lettuce                  14            n.d. - <0.4    GFR, USA/10
                             14-21         0.05 - 0.5     USA/2
    Beans, peas              14            n.d. - 0.3     S.Afr. USA/6
    Pumpkins, watermelons,   7             n.d. - 0.2     USA/11
      winter-squash                        n.d. - 0.3     USA/2
                             14            n.d.           USA/11
    Cantaloups               7-14          n.d. - 0.3     USA/1
    Summer squash            7-25          n.d. - 0.6     USA/6
                             14-25         n.d.           USA/11
    Cucumbers                14            n.d.           USA/6
    Eggplants                1-21          n.d. - 0.2     USA/6
                             14            0.6            USA/1
    Hops                     21-35         n.d. - 0.8     GFR/5
    Walnuts                  21-47         n.d.           USA/10
      (meat)
    Cotton-seed                            n.d.           USA/2
    Potatoes                 3-108         n.d.           GFR, Netherlands
                                                          USA/39
                             22-49         0.04 - 0.17    GFR/4
    Sugar beet               7-63          n.d.           GFR, USA/22

                                                                      
                             Pre-harvest   Residue        Country/
    Crop                     interval      (ppm)          number
                                                          of trials
                                                                      

    Turnips                  7-14          n.d.           USA/7
                                           0.1            USA/1
                             21-28         n.d.           USA/13
    Cereals -including:      28            n.d. - 0.26    GFR, USA/22
      Corn                   31/32         0.02 - 0.08    GFR/6
      Sorghum,               35-40         n.d.           GFR, USA/18
    Forage                   14-28         n.d. - 3.2     GFR, USA/25

      Sugar beet tops,
      turnip tops,
      sorghum forage,
      corn fodder
    Clover                   21-28         2.4 - 5.0      USA/3
    Alfalfa                  21            n.d. - 5.5     USA/5
                                                                      


    Fate of residues

    In plants

         No new data were available to amplify that summarized in 1968.

    In animals

         When 3 ppm oxydemeton-methyl in green forage was supplied to
    dairy cattle, practically no residues (40.01 ppm) were found in brain,
    heart, liver, kidney, steak and fat after a four-week feeding. When
    fed 12 ppm in forage for the same period the heart contained up to
    0.04 ppm, brain up to 0.03 ppm and steak up to 0.06 ppm. When fed 30
    ppm for seven days the following residues were determined:

         liver     - n.d.
         fat       - 0.04 ppm
         kidney    - 0.09 ppm
         heart     - 0.11 ppm
         brain     - 0.18 ppm

    In four-week feeding studies with cows, when 3 ppm oxydemetonmethyl
    was applied to the ration the residue levels in milk was lower than
    0.01 ppm. Likewise the feeding of 9 ppm in the ration produces less
    than 0.02 ppm residues in milk (Chemagro report 35556, 35557).

         No residues could be detected (below 0.001 ppm) in eggs of hens
    fed rations containing 5 ppm oxydemeton-methyl for four weeks. The
    muscle and fat of these hens was also free of residues (below 0.01
    ppm). Giblets contained 0.01 ppm-0.02 ppm (Chemagro Report 27469,
    27470).

    In soil and water

         Stability of oxydemeton-methyl in three soil types was studied.
    When 10 ppm was applied 0.05 ppm was found after 15 days. In another
    experiment residue levels decreased from 2 ppm to n.d. - 0.1 ppm after
    four weeks and later no residues were detectable.

         The effect of oxydemeton-methyl on microbial populations was
    studied (Houseworth and Tweedy, 1972). The pesticide when added to two
    types of soil at rates of 50 and 250 ppm no effect on soil
    microorganism populations could be shown over a 56-day period.

         Studies on leaching, adsorption and stability in water (Flint et
    al., 1970) showed that 3% of the applied chemical was recovered in run
    off water from sandy loam, silt loam and high organic silt loam over a
    period of five weeks.

         Leaching studies indicated that the compound leaches 30 cm into
    silt loam, and high organic silt loam following 580 mm and 1350 mm of
    rainfall, whereas sandy loam soil showed minimal retention of
    oxydemeton. The half-life of this compound in pond water outdoors at
    an average temperature of 29°C and pH 7 was 3.7 days.

    Fate of residues in storage, processing and cooking

         In sugar beet processing and corn oil deodorization, residues of
    oxydemeton-methyl, including demeton-methyl sulfone, decreased very
    markedly (Katague, 1967; Thornton, 1970b).

         When apples were processed into juice and pomace, 49% of the
    initial residues were lost (Chemagro Report 38890).

         Residues on oranges, resulting from application of
    oxydemeton-methyl, did not decrease significantly following a
    commercial washing procedure. However, all the processed orange
    products were free of residues (Olson, 1966).

         Exposure to SO2 or sun-drying did not result in losses of
    residues in peaches and prunes (Chemagro Report 21596, 21600). Washing
    of tomatoes simulating commercial preparation for market did not
    remove any significant amount of the residue (Thornton, 1973).

         Residues present on and in grapes after application of
    oxydemeton-methyl are not reduced during processing into the must and
    wine (Bayer AG, Leverkusen, Internal Report 328/67, 329/67, 348/67,
    349/67).

         During frozen storage at about -20°C, oxydemeton-methyl residues
    remain unchanged for long periods as was shown for alfalfa, apples,
    cabbage, green oat forage and raspberries (Chemagro Report 11573).

    Residues in food moving in commerce

         Out of 30 lettuce samples of German origin, one sample contained
    more than 1.0 ppm of demeton-S-methyl sulfone. Out of 91 apple samples
    of German origin, four contained residues of "demeton-methyl", viz.
    less than 0.1 ppm in three samples, and 0.1-0.5 ppm in one sample
    (Krause and Kirchhoff, 1969).

         In a survey of fruits and vegetables for organophosphorus
    insecticides carried out in 1967 in the United Kingdom, a total of 349
    samples were analysed. One out of five blackcurrant samples contained
    0.95 ppm, one out of 15 cherry samples contained 2.36 ppm, one out of
    seven radish samples contained 0.07 ppm of demeton-S-methyl. No
    demeton-methyl residues were found in any of the other samples (Dickes
    and Nicholas, 1968).

         In another study conducted in the United Kingdom, 184 samples of
    raspberries and strawberries, of which 19 were treated with
    demeton-S-methyl, were analysed for residues. All the 19 samples of
    raspberries and strawberries that had been treated with
    demeton-S-methyl were found to be free of residues (Findlay, 1972).

         The following results were provided by the New Zealand Ministry
    of Agriculture:


    A. RANDOM SAMPLING AT RETAIL LEVEL

                                                                      

                                                      Demeton-S-methyl
              Crop                                    residue levels
                                                                      

    1968   Apples and pears     1 sample in 11        Less than 0.1 ppm

    1971   Leaf vegetables      1 sample in 57        Less than 0.01 ppm

    1971   Root vegetables      2 samples in 32       Less than 0.01 ppm

    1971   Strawberries         1 sample in 7         Less than 0.01 ppm

                                                                      

    B. RESIDUES IN CROPS KNOWN TO BE TREATED WITH DEMETON-S-METHYL

                                                                      

           Crop                                  Residue levels
                                                                      

    1970   Apples            1 sample            N.D.

    1972   Strawberries      1 sample            Less than 0.005 ppm
                                                                      

    Methods of residue analysis

         Advances have been made in the development of methods for the
    analysis of demeton-methyl compounds since the evaluation in 1968.

         The basis of most methods is the oxidation of residues containing
    demeton-S-methyl and oxydemeton-methyl to the sulfone, which can then
    be determined by GLC. If permanganate is used as the oxidizing agent
    there is usually no transformation of P = S to P = O, so it is
    possible to distinguish between P = S sulfone and P = O sulfone. This
    permits conclusions to be drawn as to whether the residues present
    result from the application of demeton-S-methyl products or from the
    use of thiometon products. The same is true for demeton-S and
    disulfoton. These sulfone pairs may be clearly separated on a 1 m
    column packed with 10% DC-200 + 1% QF-1 on 80/100 mesh Gas Chrom Q at
    195°C (Wagner, 1973). The following retention times are obtained:

         demeton-S-methyl sulfone      3.75 min
         thiometon sulfone             4.75 min
         demeton-S-sulfone             5.0 min
         disulfoton sulfone            6.15 min

         The determination of oxydemeton and demeton-S-methyl sulfone in
    lettuce and sugar beets is described by Thornton and Olson (1971). A
    sensitive GLC method for all the three compounds in sorghum foliage
    and wheat plants is described by Thornton and Anderson (1968) who
    reports a limit of determination of 0.05 ppm.

         Determination of oxydemeton and metabolite residues in
    cotton-seed and walnuts is described by Olson (1971a)  Limit of
    determination of the method for these crops is 0.01 ppm.

         No interferences were observed by Olson (1971b) and Thornton
    (1970c), Thornton and Olson (1971) when all organophosphorus
    pesticides registered in the United States of America were examined.
    If so, they could be resolved by the standard or alternate procedures.
    A GLC procedure for residues in poultry and eggs is described by
    Thornton (1970a).

         The determination of oxydemeton-methyl and other phosphorus
    compounds in the soil is described by Olson (1970b). Limit of the
    method - 0.1 ppm.

         A multi-residue scheme for organophosphorus pesticides residue
    analyses in total diet samples was described by Abbot et al. (1970).
    It included three different extraction and clean-up procedures for
    seven commodity groups. Thirty-one pesticides and some of their
    metabolites (among them demeton-S-methyl and demeton-S-methyl) were
    recoverable by this method with a limit of determination of
    approximately 0.01 ppm for most compounds.

    National tolerances and safety intervals

         Unless otherwise stated, the given tolerance levels and safety
    intervals apply to both demeton-S-methyl (I) and oxydemeton-methyl
    (II).


                                                                      
                                                              Safety
    Country       Crop                           Tolerance    interval
                                                 in ppm       in days
                                                                      

    Australia     Fruit, vegetables, cereals     0.5
                  General                                     21 (I)

    Austria       General                                     35

    Belgium       Fruit, vegetables excl.        0.4
                  potatoes
                  General                                     28

    Denmark       General except lettuce,                     28 (II)
                  spinach and other short
                  season crops

    Finland       General except vegetables                   35 (II)

    France        General except vegetables                   21 (II)
                  and strawberries

    Germany,      Fruit, vegetables, field                    21
    Federal       crops incl. fodder crops,
    Republic of   application under glass
                  generally
                  Vegetables excl. carrots,      0.4a
                  fruit, sugar beets
                  Cereals, potatoes              0.2a
                  Other food crops               0.05a

    (cont'd)
                                                                      
                                                              Safety
    Country       Crop                           Tolerance    interval
                                                 in ppm       in days
                                                                      

    Hungary       General                        0.5          30 (I)

    Italy         General                        0.4b         20

    Korea         Fruit, vegetables,                          30 (I)
                  potatoes, tobacco, fodder
                  crops

    Morocco       General except vegetables                   21 (I)

    Netherlands   General                        0.4a
                  Potatoes                       0.1a
                  Fruit incl. soft fruit,                     28
                  beans, peas, brassicas,
                  potatoes

    New Zealand   General from Oct.-March        0.4          21
                  General from April-Sept.       0.4          35

    Norway        General                                     28 (I)

    Poland        Fruit, vegetables, legumes                  30 (II)
                  (no vegetables), root
                  crops and other field
                  crops
                  Fruit, vegetables, legumes                  42 (I)
                  (no vegetables), root
                  crops and other field crops
                  Apples, pears, plums                        Apply up to
                                                              14 days post
                                                              blossom
                  Sweet cherries, currants,                   Established
                  gooseberries, garden                        by time of
                  strawberries, raspberries                   application
                  Fruit and vegetables           0.4

    Portugal      General                                     35 (II)

    South         General                        2.0
    Africa        Beans, crucifers generally                  10
                  Brussels sprouts                            14
                  Fruit, potatoes, tomatoes                   21
                  Cueurbits                                   21 (II)
                  Brinjals, peppers                           14 (I)
                  Kafir corn, onions, wheat,                  21 (I)
                  groundnuts, cotton, maize


 
    (cont'd)
                                                                      
                                                              Safety
    Country       Crop                           Tolerance    interval
                                                 in ppm       in days
                                                                      

    Spain         Cereals, sugar beets                        30 (II)
                  Cotton                                      35 (II)
                  Fruit                                       Apply only
                                                              up to petal
                                                              fall or
                                                              post-harvest
                                                              (II)

    Sweden        General                                     28

    Switzerland   Leafy and fruiting             0.4b
                  vegetables, legumes, fruit
                  crops, grapes, hops
                  Fruit, grapes, sugar beets                  42 (II)
                  Field beans                                 Before 
                                                              flowering
                                                              begins (II)

    USSR          Fruits                         0.7 (I)
                  Fodder                         1.0

    United        Wheat, barley                               14 (I)
    Kingdom       Mangold, fodder beets                       10 (I)
                  (for clamping)
                  Fodder crops generally                      21 (I)
                  All other crops                             21 (I)

    United        Fruits, general                1.0
    States        Melons, pears                  0.3
    of America    Vegetables, general            1.0
                  Potatoes                       0.1
                  Sugar beets                    0.3
                  Sugar beets tops               0.5
                  Turnips                        0.3
                  Winter squash                  0.3
                  Pumpkins                       0.3
                  Cotton seed                    0.1
                  Walnuts                        0.3
                  Alfalfa (green)                5.0
                  Alfalfa (hay and chaff)        11.0
                  Clover (green)                 5.0
                  Clover (hay and chaff)         11.0
                  Corn fodder and forage         3.0

     
    (cont'd)
                                                                      
                                                              Safety
    Country       Crop                           Tolerance    interval
                                                 in ppm       in days
                                                                      
                  Corn grain, fresh corn         0.5
                  incl. sweet corn (kernels,
                  plus cob with husk
                  removed)

 
    Yugoslavia    Fruit, grapes, field                        28 (II)
                  crops, hops
                                                                      

    a Sum of demeton-S-methyl (I), oxydemeton-methyl (II) and 
      demeton-S-methylsulfone (III) calculated as demeton-S-methyl (I).

    b Total as demeton-S-methyl (I).

    Appraisal

         Since the evaluation of the oxydemeton-methyl in 1965, 1967,
    1968, further data have become available on the following compounds:

         I   - demeton-S-methyl;
         II  - oxydemeton-methyl; and
         III - demeton-S-methyl sulfone.

    which are systemic organophosphorus insecticides and acaricides used
    individually for pre-harvest treatment of a wide range of crops in
    many countries.

         One to five applications are recommended at rates ranging from
    0.1-0.6 kg/ha depending on the crop.

         Compounds II and III are also the oxidative metabolites of
    demeton-S-methyl. Following treatments with either compounds I or II,
    the residues in the crops consist of oxidized derivatives of compounds
    I and/or II.

         Residue data were available from the United States of America,
    Germany, United Kingdom, South Africa and Netherlands from supervised
    trials on fruit, vegetables, field crops and fodder, and on the
    feeding of animals. Information on the fate of residues in storage and
    processing of some crops was available as was information on the fate
    of residues in soil and pond water. Data on residues in foodstuffs
    moving in commerce were also considered.

         Available multi-residue gas-chromatographic procedures are
    suitable for regulatory purposes but it is essential to oxidize all
    components of the residue to compound III (sulfone) in order to
    increase the accuracy.

    RECOMMENDATIONS

    Tolerances

         The following recommendations are based on pre-harvest intervals
    of 14-28 days.

         Animal foodstuffs (green)                         5 ppm
            "        "     (dry)                           10 ppm
         Currants (red and black), grapes                  2 ppm
         Apples, peaches, plums                            1 ppm
         Blackberries, citrus fruits, gooseberries,        0.5 ppm
           lettuce, pears, raspberries, strawberries,
           summer squash
         Beans, broccoli, brussels sprouts,                0.2 ppm
           cabbage, cantaloupes, cauliflower,
           cereals, cucumbers, eggplants, peas,
           potatoes, pumpkins, raw cereals,
           watermelons, winter squash
         Cotton-seed, sugar beets, turnips                 0.1 ppm
         Eggs, fat and meat of cattle,                     0.05* ppm
           sheep, pigs, poultry, milk and milk
           products, nuts (kernal)

         These tolerances are to apply to the sum of the residues of
    demeton-S-methyl, oxydemeton-methyl, and demeton-S-methyl sulfone,
    determined as the sulfone and calculated as demeton-S-methyl.

    FURTHER WORK OR INFORMATION

    Desirable

    1.   Studies to elucidate fatty degeneration in liver at high doses.

    2.   Information on residues in animal tissues from the feeding of
         demeton-methyl group compounds, in the form of plant residues, to
         domestic animals other than cows and chickens.

              
    * At or about the limit of determination.

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    Hibbs, C.M. and Nelson, D.L. (1967) "Histologic Evaluation of 
    Meta-Systox R Treated Rats". Unpublished report submitted by Bayer
    A.G.

    Houseworth, L.D. and Tweedy, B.G. (1972) Effect of META-SYSTOX-R on
    microbial populations. Chemagro-Report No. 34 991

    Houseworth, L.D. and Tweedy, B.G. (1973) Report on parent leaching 
    studies for METASYSTOX-R. Chemagro-Report No. 37 181

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    demeton-methyl residues in fruits and vegetables. Analyst, 87:
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    Katague, D.B. (1967) The effect of processing on META-SYSTOX-R
    residues in sugar beets. Chemagro-Report No. 20 686

    Kimmerle, G. (1961) "Protective action of FAM against R 2170 poisoning
    and neurotoxic effect of R 2170". Unpublished report submitted by
    Bayer A.G.

    Kimmerle, G. (1963) "Meta-Systox (i)". Unpublished report submitted by
    Bayer A.G.

    Kimmerle, G. (1966a) "E 154 (88, 5%)/Antidetwirkung". Unpublished
    report submitted by Bayer A.G.

    Kimmerle, G. (1966b) "Metasystox R/Antidotwirkung (Ht-Nr. 3653)".
    Unpublished report submitted by Bayer A.G.

    Kimmerle, G. (1966c) "Toxicological Studies on Active Ingredient Saver
    20 315". Unpublished report submitted by Bayer A.G.

    Kimmerle, G. (1972) "Acute Toxicity of ERA 3886 in Combination with S
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    A.G.

    Kimmerle, G. and Lurks, D. (1968) "Toxicology of insecticidal
    organophosphates". Fflanzenschutz-Nachrichten Bayer 1/68, 21: 111-142

    Klimmer, O.R. (1960) "Opinion on the toxicity of the substance 'R
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    Institut der Universitat, Bonn

    Klimmer, O.R. (1961) "Gutachten uber die chronische orale Toxizitat
    von Metasystox der Farbenfabriken Bayer A.G., Leverkusen". Unpublished
    report from the Pharm. Institut der Universitat, Bonn

    Klimmer, O.R. (1964) "Bestimmung der akuten oralen Toxizitat von 
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    Klimmer, O.R. (1965) "Insecticide BAYER 20 315/Toxicological Studies".
    Unpublished report from the Pharm. Institut der Universitat, Bonn

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    des neuen Kontaktinsekticides 0,0 
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    Klotzsche, C. (1964) "Zur toxikologischen Prufung neuer insecticider
    Phosphorsaureester". Int. Arch. f. Gewerbepath, u. Gewerbehyg. 21:
    92-106

    Krause, Ch. and Kirchhoff, J. (1969) Organophosphatruckstande auf
    Marktproben von Obst und Gemuse sowie auf Getreideerzeugnissen.
    Nachrichtenbl. Dtsch. Pflanzenschutzdienstes, 21: 81-84

    Ladd, R., Jenkins, D.H., Keplinger, M.L. and Fancher, O.E. (1971)
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    Rabbits".

    Laws, E.Q. and Webley, D.J. (1959) Determination of demeton methyl
    residues in plant material. Analyst, 84: 28-32

    Loeffler, W.W. (1963) Colorimetric determination of METASYSTOX R
    residues in plant material. Chemagro-Report No. 11 476

    Unpublished report from Industrial Biotest Laboratories Inc.

    Lorke, D. and Kimmerle, G. (1969) "The Action of Reactivators in
    Phosphoric-Acid-Ester Poisoning". Naunym Schmiedebergs Arch. Pharmak.
    exp. Path. 263: 237

    Loser, E. (1971a) "R 2170 (Metasystox R Active Ingredient)/Subchronic
    Toxicological Studies on Rats". Unpublished report submitted by Bayer
    A.G.

    Loser, E. (1971b) "E 158 (metaisosystoxulfone)/Subchronic
    Toxicolological Studies on Rats". Unpublished report submitted by
    Bayer A.G.

    Loser, E. (1972) "Metasystox R (R 2170) - Metaisosystoxsulfone, (E
    158)/Vergleichende Untersuchungen zur Cholinesterase-Hemung bei
    Ratten", Unpublished report submitted by Bayer A.G.

    March, R.E., Metcalf, R.L., Fukuto, T.R. and Maxon, M.G. (1955)
    Metabolism of Systox in the white mouse and American cockroach. J.
    Econ. Entomol. 48: 355-363

    Metcalf, R.L., Fukuto, T.R., March, R.B. and Stafford, E.M. (1956) The
    systemic behaviour of Systox thiol isomer sulfoxide and methosulfate
    in plants. J. Econ. Entomol. 49: 738-741

    Metealf, R.L., March, R.B., Fukuto, T.R. and Maxon, M. (1954) The
    behaviour of Systox-isomers in bean and citrus plants. J. Econ.
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    Metcalf, R.L., March, R.B., Pukuto, T.R. and Maxon, M.G. (1955) The
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    van der Merve, J.H. and Taylor, W.B. (1971) Gas chromatographic 
    determination of demeton-S-methyl residues in plant material.
    Pflanzenschutz-Nachrichten Bayer, 24: 259-264

    Mühlmann, R. and Tietz, H. (1956) "Das chemische Verhalten von
    Methylisosystox in der lebenden Pflanze und das sich daraus ergebende
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    New Zealand Ministry of Agriculture. (1973) Information reported to
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    Newman, A.J. and Urwin, C. (1972) "Pathology Report of E 158 Rat
    Study". Unpublished report from the Huntingdon Res. Centre, England

    Niessen, H., Tietz, H., Hecht, G. and Kimmerle, G. (1963) "Uber
    Vorkonmen von Sulfoniumverbindungen in Metasystox (i) und Metasystox R
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    Olson, T.J. (1966) The effect of processing on META-SYSTOX-R residues
    in oranges and orange products. Chemagro-Report No. 18 586

    Olson, T.J. (1969) A confirmatory gas chromatographic procedure for
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    Addendum Chemagro-Report No. 28 504 (1970)

    Olson, T.J. (1970a) A study of the possible interferences of other
    pesticides with the analytical method for METASYSTOX-R on crops.
    Chemagro-Report No. 21 463

    Olson, T.J. (1970b) Determination of DASANIT, GUTHION, META-SYSTOX-R3
    NEXACUR and TRICHLORFON in soil by thermionic emission gas
    chromatography. Chemagro-Report No. 27 835

    Olson, T.J. (1971a) Determination of META-SYSTOX-R residues in
    cottonseed and walnuts by thermionic emission gas chromatography.
    Chemagro-Report No. 21 590

    Olson, T.J. (1971b) An interference study for the META-SYSTOX-R
    residue method for crops. Chemagro-Report No. 30 957

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    Unpublished report from Industrial Biotest Laboratories, Inc.

    Root, M., Cowan, J. and Doull, J. (1963) "Determination of the Safe 
    Dietary Level for Metasystox-R in Dogs". Unpublished report from the
    University of Chicago

    Root, M., Meskauskas, J., Kinoshita, F., Flynn, M. and Grohs, D.
    (1967a)  "Subacute Oral Toxicity of Metasystox-R to Male and Female
    Rats". Unpublished report from the University of Chicago

    Root, M. and Meskauskas, J. (1968) "Addendum to a Report on Subacute
    Oral Toxicity of Metasystox-R to Male and Female Rats". Unpublished
    report from the University of Chicago

    Root, M., Meskauskas, J., Kinoshita, F., Flynn, M. and Grohs, D.
    (1967b)  "Subacute Oral Toxicity of Metasystox-R to Male and Female
    Dogs". Unpublished report from the University of Chicago

    Root, M. (1969) "Addendum to Subacute Oral Toxicity of Metasystox-R to
    Male and Female Dogs". Unpublished report from the University of
    Chicago

    Root, M.. Meskauskasy J., Kinoshita, F., Flynn, M. and Kompf, C.
    (1968)  "Subacute Oral Toxicity of Metasystox  R to Male and Female
    Rats". Unpublished report from the University of Chicago

    Root, M., Meskauskas, J., Kinoshita, F. and Flynn, M. (1970) "Subacute
    Oral Toxicity of Metasystox-R to Male and Female Dogs". Unpublished
    report from the University of Chicago

    Root, M.S. and Doull, J. (1972) "Comparative Subacute Oral Toxicity of
    Some Organic Phosphates in Rats and Dogs". (5th Annual Meeting - 29
    June 1972 -  reviewed by abstract only)

    Su, M.Q., Kinoshita, F.K., Frawley, J.P. and DuBois, K.P. (1971)
    "Comparative Inhibition of Aliesterase and Cholinesterase in Rats Fed
    Eighteen Organophosphorus Insecticides". Toxicol. and Appl. Pharm.
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    plants. A survey of results obtained with 32-P labelled Schradan and
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    absorption, breakdown and systemic behaviour in plants of
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    Thomas, W.D.E. and Glynne Jones, G.D. (1955) The systemic properties
    of diethyl-S-2-(ethylthioethyl) phosphorothiolate (demeton-S) with
    reference to the contamination of nectar. Ann. Appl. Biol. 43:
    182-191

    Thornton, J.S. (1970a) A confirmatory gas chromatographic procedure
    for META-SYSTOX-R in poultry and eggs. Chemagro-Report No. 27 085

    Thornton, J.S. (1970b) Effect of the oil doodorization process on
    residues of METASYSTOX-R and METASYSTOX-R sulfone in corn oil
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    Thornton, J.S. (1970c) A study of the possible interferences of other
    pesticides with the analytical method for META-SYSTOX-R on crops. I.
    Test for the compounds registered on mint. Chemagro-Report No. 29 063

    Thornton, J.S. (1973) Effect of washing on residues in tomatoes
    treated with METASYSTOX-R. Chemagro-Report No. 37 332

    Thornton, J.S. and Anderson, C.A. (1968) Determination of residues of
    Di-Syston and metabolites by thermionic emission flame gas
    chromatography. J. Agr. Food Chem. 16: 895-898

    Thornton, J.S. and Olson, T.J. (1971) Determination of META-SYSTOX-R
    residues in lettuce and sugar beets by thermionic emission gas
    chromatography. Chemagro-Report No. 21 000

    Thornton, J.S. and Yoksh, R.M. (1970) Determination of META-SYSTOX-R
    residues in poultry tissues and eggs by thermionic emission flame gas
    chromatography. Chemagro-Report No. 27 004

 

    Tietz, H. and Frehse, H. (1960) Methods zur Bestimmung von Rückstanden
    der systemischen Insektizide der Metasystox Gruppe in pflanzlichem
    Material. Hofeben-Briefe, 13, 212-221

    Vandekar, M. (1958) "The Toxic Properties of Demeton-Methyl
    (Metasystox) and Some Related Compounds". Brit. J. Industr. Med. 15:
    158-167 (Cited in FAO/WHO, 1965, 1968)

    Vince, A.A. and Spicer, J.F. (1971) "Pathology Report on R 2170 
    (Metasystox-R active substance) Sub-Chronic Toxicological Studies in
    Rats". Unpublished report from the Huntingdon Res. Centre

    Wagner, K. (1973) Unpublished. Bayer A.G., Pflanzenschutz AT, Biol.
    Forschung, Institut fur Ruckstandsanalytik

    Wirth, W. (1958) "Zur Wirkung System-insecticider Phosphorsaure Ester
    in Warmbluter-Stoffwechsel". Naunyn SchmiedebergIs Arch. exp. Path. u.
    Pharmak. 234: 352-363
 
    Wren, D.B. and Nelson, D.L. (1969) "Histologic Evaluation of
    Metasystox-R Treated Rats". Unpublished report from the Chemagro
    Corporation, submitted by Bayer A.G.

    Wren, W.B. (1970) "Microscopic Findings in the Tissues of Male and
    Female Dogs Administered Metasystox-R Orally (subacute toxicity) 150
    ppm". Unpublished report submitted by Bayer A.G.

    Wren, W.B., Hibbs, C. and Nelson, D.L. (1968) "Subacute Dermal
    Toxicity of the Metasystox-R Formulation to Rats, Histologic
    Evaluation of Metasystox-R Treated Rats". Unpublished report from
    Chemagro Corporation, submitted by Bayer A.G.
    


    See Also:
       Toxicological Abbreviations
       Demeton-S-methyl and related compounds (Pesticide residues in food: 1984 evaluations)
       Demeton-S-Methyl and Related Compounds (Pesticide residues in food: 1989 evaluations Part II Toxicology)